A normal bone metabolism involves an equilibrium between the level of bone resorption by osteoclasts and the level of bone formation by osteoblasts, by which a homeostasis is maintained. A metabolic bone disease is considered to be developed once such a balance between the bone resorption and the bone formation is lost. This disease includes osteoporosis, osteitis fibrosa (hyperparathyroidism), osteomalacia and Paget's disease which affects the parameters of systemic bone metabolism. The osteoporosis is observed frequently in postmenoposal women or old men, and causes a pain such as a lumbar pain and a bone fracture, and is seriously problematic especially in older patients whose bone fracture readily leads to a systemic weakness and a dementia. For the purpose of treating or preventing such a bone disease, a calcium preparation, active vitamin D3 preparation, calcitonin preparation and estrogen preparation are employed.
However, most of these therapeutic agents do not exhibit marked bone formation-stimulating effect, although they were reported to have a bone resorption-inhibiting effect. A bone-forming agent is highly desired especially in a senile osteoporosis which was reported to be caused mainly by a reduction in the bone formation due to a reduction in the bone turnover (New Eng. J. Med. 314, P1676, (1986)).
Recently, a benzothiepin derivative (for example, JP-A-8-231569) and an N-quinolylanthranilic acid derivative (for example; JP-A-9-188665) having an alkaline phosphatase-inducing activity were reported to be useful in promoting osteogenesis and in treating a metabolic bone disease. Nevertheless, their clinical utility is unknown.
On the other hand, there are the following reports with regard to triazolopyridazine derivatives (symbols in the description represent the symbols in Formula (I) of the invention described below). However, any of these references and patent specifications does not contain any disclosure or suggestion of an osteogenesis-promoting effect.
(1) An antibacterial compound wherein Ra and Rb are taken together with an adjacent N atom to form a piperidino, E is a single bond, and R is piperidino disclosed in U.S. Pat. No. 3,957,766; a method for synthesizing a compound wherein R is an unsubstituted phenyl disclosed in Tetrahedron, 22(7), 2073–9 (1966); a structure of a compound wherein R is p-(trifluoromethyl)phenyl or p-chlorophenyl disclosed in CAS Registry File under the codes RN=289651-67-8 and 202820-26-6; and a compound wherein R is o-nitrophenyl disclosed in SPECS catalog under Refcode:AG-690/3073051.
(2) A triazolopyridazine derivative having a bronchodilating effect which is a compound wherein Ra and Rb are taken together with an adjacent N atom to form a 4-methyl-1-piperazinyl, E is a single bond, and R is an unsubstituted phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-chlorophenyl, p-chlorophenyl or m-nitrophenyl, disclosed in German Patent 2,444,322 and JP-A-50-58092.
(3) An antibacterial compound wherein R is an optionally substituted imidazolyl disclosed in German Patents 2,261,693, 2,254,873 and 2,215,999; an antibacterial compound wherein R is 5-nitro-2-furyl or 5-nitro-2-thienyl disclosed in German Patent publications 2,161,586, 2,161,587 and 2,113,438.
(4) The structure of a compound wherein Ra is H, Rb is cyclopropyl, E is a single bond and R is a p-(trifluoromethyl)phenyl disclosed in CAS Registry File under the codes RN=289651-68-9.
(5) an antihypertensive compound wherein Ra is a methyl, Rb is a 2-hydroxy-propyl, E is a single bond and R is a 3-pyridyl disclosed in Farmaco. Ed. Sci., 34(4), 299–310 (1979).
In order to reduce a pain such as a lumbar pain or to reduce the risk of bone fracture in a metabolic bone disease such as osteoporosis, it is required to increase the bone mass and the bone strength, and thus it is highly desired to develop a clinically useful bone-forming agent having an ability of stimulating the bone formation by osteoblasts which is considered to be surely effective.